In the field of gadolinium-containing contrast agents, gadobutrol is commercially available under the trade name of Gadovist or Gadavist all over the world.
Gadobutrol is a nonionic complex of gadolinium (III) and a macrocyclic ligand 10-(2,3-dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (butrol), and functions to shorten the relaxation time of protons in tissue water at clinically recommended doses.
However, in most gadolinium-containing contrast agents, including gadobutrol, it has come to be known that the use of an excess of complex-forming ligand therein in the form of a calcium complex is favorable. The calcium complex plays a role in preventing the release of free gadolinium from, the formulation (e.g. by storage for many years through re-complexation with foreign ions derived from glass).
Calcobutrol, represented by Chemical Formula 1 below, is a complex of calcium and 10-(2,3-dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (butrol), and is able to prevent the release of free gadolinium from gadobutrol, thus solving the problem of toxicity of gadolinium ions, and is contained as an additive (calcobutrol sodium salt) in Gadovist.

The synthesis of calcobutrol is described in detail in the literature (Inorg. Chem. 1997, 36, 6086-6093). However, the process disclosed in the above literature does not provide calcobutrol having high purity. When faithfully reproducing the process of Scheme 3 of the above literature, a material having a purity of about 90% through HPLC (stationary phase: Hypersil phenyl (5 μm) of SHANDON; mobile phase: acetonitrile/borate buffer (pH 8) (volume ratio 20/100); detection: UV detector (200 nm); injection volume: 10 μL) is obtained.
Meanwhile, a ligand (butrol) obtainable during the synthesis route of gadobutrol cannot be purified through crystallization, making it impossible to attain the high purity necessary for directly transferring it to a calcium complex. A neutral gadolinium complex, namely gadobutrol, may be obtained at very high purity (>99.7%) through very effective crystallization following purification in an ion exchange column after the reaction of butrol and gadolinium. However, calcobutrol is not easy to purify because of the extra acid functionality. Hence, the route for directly preparing calcobutrol from butrol is considered unsuitable in terms of purity.
With the goal of solving the above problem, Korean Patent Application Publication No. 2011-0058746 discloses a method of preparing highly pure calcobutrol, comprising decomplexing already-obtained gadobutrol, serving as a starting material, removing gadolinium ions to give butrol, and then complexing the butrol with calcium. However, the method of the above patent is problematic because gadobutrol is used as an intermediate in the synthesis of calcobutrol, thus negating economic benefits and complicating the preparation process.
Accordingly, it is required to develop a novel method of preparing highly pure calcobutrol at a high yield through simple, economic and mild preparation processing.